Insulin resistance and disordered carbohydrate and lipid metabolism is widely recognized in uremia. The role of the liver in these metabolic derangements is not well established. Where diabetes mellitus is complicated with uremia, a complex metabolic situtation occurs associated with a very high morbidity and mortality. Information, at the cellular level, on this high risk population is suprisingly absent. In an attempt to study these problems, I have developed two novel chronic uremic diabetic and nondiabetic and continual peritoneal dialysis rat models. Freshly isolated hepatocytes and primary culture of rat hepatocytes will be used. Insulin and glucogon-hepatocyte binding, internalization and degradation will be studied. These data will be correlated with specific insulin and glucagon biological responses to better understand the relationship between these processes. Glucose utilization and production and the regulation by insulin will be analyzed to get insight into the mechanism(s) of glucose intolerance in uremia. Finally the contribution of the liver to the hyperlipidemia of uremia will be directly assessed by measuring lipid synthesis and its sensitivity to insulin. The importance of uremic "factors" in the metabolic derangements to be defined with the freshly isolated hepatocytes will be studied in vitro with the use of primary culture of rat hepatocytes technique by performing cross-over studies with hepatocytes from uremic and normal rats incubated with normal and uremic serum. Also the role of dialysis on insulin and glucagon action can be invested with continous peritoneal dialysis rat model. The long term objectives of this project are to improve our understanding of the interrelationships between insulin processing and insulin action in the liver, the mechanism(s) of insulin resistance in uremia and the role of the liver in the abnormal carbohydrate and lipid metabolism encounter in uremia.